From March 1, 2002 through December 31, 2008, 61,749 patients were listed for single-organ liver transplantation through the UNOS registry. Of these patients, 12,585 (36%) females and 22,126 (64%) males met the inclusion criteria (). Characteristics of the study cohort of 34,711 liver transplant candidates are shown in . At listing, females were older, of shorter height and lower weight, and more likely to be of African-American or Hispanic race. A significantly greater proportion of females were transplanted in UNOS regions with medium or high mean MELD scores at transplantation. Females were more likely to be listed for NAFLD or autoimmune etiologies of liver disease. Serum creatinine, eGFR, and MELD scores at listing also differed.
Flow of Patients Listed for Liver Transplantation. Abbreviations: HCC, hepatocellular carcinoma; FHF, fulminant hepatic failure; AHN, acute hepatic necrosis; Cr, serum creatinine at listing.
Characteristics of Patients Listed for Liver Transplantation in the United States from March 1, 2002 through December 31, 2008
During the follow-up period, 2,770 (22%) females and 4,340 (20%) males died or became too sick for transplantation; 4,894 (39%) females and 10,059 (46%) males received a deceased donor liver transplant; and 1,359 (11%) females and 2,241 (10%) males were removed for other reasons.
Cumulative incidence of wait-list mortality by gender is shown in . In this initial analysis adjusting only for MELD score, females were at an estimated 19% (HR, 1.19; 95% CI, 1.13-1.25; p<0.001; ) increased risk of dying or becoming too sick for transplant, compared with males. Adjustment for MELD, age, African-American race, etiology of cirrhosis, region risk group, ABO group, and significant interactions between these covariates explained only a small part of the association between gender and wait-list mortality risk (). However, additional adjustment for height almost completely explained the remaining association ().
Cumulative incidence curves comparing the risk of wait -list mortality in females compared with males, adjusted for MELD only.
Adjusted Risk of Wait-list Mortality for Females Compared with Males.
The majority of women were distributed in the lowest quartile of the height distribution of wait-list candidates (). Compared to patients in the uppermost quartile of height, mortality rates were 8% higher in the middle two quartiles (HR, 1.08; 95% CI, 1.02-1.15; p=0.01), and 24% higher in the lowest quartile of height (HR, 1.24; 95% CI, 1.14-1.36; p<0.001).
Height of Female and Male Wait-List Candidates in the United States.
In an exploratory analysis, adjustment for weight rather than height as a marker for body size explained only a small part of the adjusted association with gender (adjusted HR, 1.13; 95% CI, 1.07-1.19; p<0.001). Further exploratory analysis revealed that the relative hazard of wait-list mortality in females compared to males was larger in patients listed with worse renal function, whether estimated by serum creatinine or eGFR. Specifically, after adjusting for INR and bilirubin, the relative hazard of wait-list mortality by gender increased with increases in creatinine (p for interaction <0.001; ). Similarly, decreases in eGFR, representing worse renal function, were associated with increases in the gender disparity in wait-list mortality (; p for interaction <0.001).
Relative Hazard of Wait-List Mortality for Females Compared to Males By A) Creatinine at Listing (mg/dL) and B) GFR at Listing (ml/min).
We next explored whether delays in transplantation specific to height or gender could explain our findings. In a competing risks analysis of transplantation, rates were 17% lower among women (HR, 0.83; 95% CI, 0.80-0.86; p<0.001) after adjustment for MELD, age, region, and blood group. After further adjustment for quartile of height, adjusted transplantation rates remained 12% lower among women (HR, 0.88; 95% CI, 0.83-0.92; p<0.001). As compared to patients in the uppermost quartile of height, transplantation rates were 3% lower (HR, 0.97; 95% CI, 0.93-1.01; p=0.12) in the middle two quartiles and 11% lower (HR, 0.89; 95% CI, 0.83-0.95; p<0.001) in the shortest quartile.
To further investigate the association between gender and height on wait-list events, median MELD scores at each event were evaluated (). Female wait-list candidates in the short and average height categories were listed with a lower median MELD score compared to male wait-list candidates, but died at similar median MELD scores. In contrast, short and average height female candidates were transplanted at a slightly lower MELD score than males of similar heights, although this only met the pre-specified threshold for statistical significance (p<0.05) within the average height category. There was a statistically significant gender difference in the median MELD score at the time of other removal among those of average height.
MELD Scores by Height Categories at Listing, Death, Transplant, and Other Removal